A basic knowledge of how we age is essential for our understanding of age-related impairments in brain function that lead to major personal and economic problems for older citizens. In addition, changes in the brain considered part of normal aging may contribute to the onset and progression of age-related neurodegenerative diseases of the central nervous system (CNS), the classic examples of which are Alzheimer's, Huntington's and Parkinson's diseases. However, while many of the neurodegenerative diseases of the CNS have a characteristic age of onset after midlife, it is unclear what role age-related changes in the morphological, biochemical and electrophysiological properties of CNS neurons play in the onset and progression of a disease process. The proposed program project targets this gap in our knowledge of the aging brain by testing hypotheses about mechanisms of age-related changes in brain function. We propose an integrated program of basic research to examine the cellular and molecular mechanisms involved in brain aging, with particular emphasis on the substantia nigra and striatum, structures especially vulnerable in Parkinson's and Huntington's diseases. The study of reactive synaptogenesis, neuron death and functional adaptability to aging and injury represent the main areas of focus on our renewal application. Furthermore, we propose to manipulate age-related changes in dopaminergic function using chronic dietary restriction or treatment with the dopamine agonist pergolide. These studies will investigate the cellular and molecular events associated with oxidative stress in aging, with an emphasis on GFAP expression and other glial responses that we have documented in response to neurodegeneration. In addition, we will analyze the expression of several recently discovered genes, including apoJ, SCG-10, BDNF, GDNF, which seem to play key roles in processes determining cell survival and plasticity. The proposed experiments will help to understand the cellular and molecular mechanisms that lead to cell death in some regions of the aged brain and will provide the basis for the development of future therapeutic strategies aimed at the treatment of age-related neurodegenerative diseases of the CNS.